1358581-37-9

Basic information

• Product Name: (2S,3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)Methyl)-4-Methylphenyl)-tetrahydro-6-(hydroxyMethyl)-2-Methoxy-2H-pyran-3,4,5-triol
• Synonyms: (2S,3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)Methyl)-4-Methylphenyl)-tetrahydro-6-(hydroxyMethyl)-2-Methoxy-2H-pyran-3,4,5-triol;Methyl 1-C-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-alpha-D-glucopyranoside;(2S,3R,4S,5S,6R)-2-[3-[[5-(4-fluorophenyl)-2-thienyl]Methyl]-4-Methyl-phenyl]-6-(hydroxyMethyl)-2-Methoxy-tetrahydropyran-3,4,5-triol;(2S,3R,4S,5S,6R)-2-(3-((5-(4-Fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol;2-Methoxy Canagliflozin
• CAS NO: 1358581-37-9
• Molecular Formula: C₂₅H₂₇FO₆S
• Molecular Weight: 474.5416832
• Mol File: 1358581-37-9.mol

Chemical Properties

• Boiling Point: 644.5±55.0 °C(Predicted)
• Appearance: /
• Density: 1.41±0.1 g/cm3(Predicted)
• PKA: 12.73±0.70(Predicted)
• CAS DataBase Reference: (2S,3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)Methyl)-4-Methylphenyl)-tetrahydro-6-(hydroxyMethyl)-2-Methoxy-2H-pyran-3,4,5-triol(CAS DataBase Reference)
• NIST Chemistry Reference: (2S,3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)Methyl)-4-Methylphenyl)-tetrahydro-6-(hydroxyMethyl)-2-Methoxy-2H-pyran-3,4,5-triol(1358581-37-9)
• EPA Substance Registry System: (2S,3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)Methyl)-4-Methylphenyl)-tetrahydro-6-(hydroxyMethyl)-2-Methoxy-2H-pyran-3,4,5-triol(1358581-37-9)

Safety Data

• Hazardous Substances Data: 1358581-37-9(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
(2S,3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)Methyl)-4-Methylphenyl)-tetrahydro-6-(hydroxyMethyl)-2-Methoxy-2H-pyran-3,4,5-triol is used as an impurity in the synthesis of drugs, such as Canagliflozin (C175190). Canagliflozin is a sodium/glucose cotransporter 2 (SGLT2) inhibitor, which has been shown to dose-dependently reduce the renal threshold for glucose excretion and increase urinary glucose excretion. It is a candidate for the treatment of type 2 diabetes and obesity.
Used in Chemical Industry:
(2S,3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)Methyl)-4-Methylphenyl)-tetrahydro-6-(hydroxyMethyl)-2-Methoxy-2H-pyran-3,4,5-triol may also have potential applications in the chemical industry, where its unique structure and functional groups could be utilized for the development of new materials or chemical processes. However, more information on its specific properties and reactivity would be needed to determine its exact applications in this field.

Synthetic route

methanol (67-56-1) + (2R,3S,4R,5R)-1-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-2,3,4,5,6-pentahydroxyhexan-1-one → (2S,3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxylmethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1358581-37-9)

Conditions	Yield
With methanesulfonic acid Large scale;	96.6%
With methanesulfonic acid at 15℃; for 3h; Industrial scale;

methanol (67-56-1) + 2-[(5-bromo-2-methyl-phenyl)methyl]-5-(4-fluorophenyl)thiophene (1030825-20-7) + (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one (32469-28-6, 55515-28-1, 55515-29-2, 32384-65-9) → (2S,3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxylmethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1358581-37-9)

Conditions

Yield

Stage #1: 3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl bromide With n-butyllithium In tetrahydrofuran; hexane; toluene at -78℃; for 1h; Stage #2: (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one In tetrahydrofuran; hexane; toluene at -78℃; for 3h; Stage #3: methanol With methanesulfonic acid In tetrahydrofuran; hexane; toluene at -78 - 40℃; for 10h;

83%

2-[(5-bromo-2-methyl-phenyl)methyl]-5-(4-fluorophenyl)thiophene (1030825-20-7) + C70H82O6Si4 → (2S,3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxylmethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1358581-37-9)

Conditions	Yield
With sec.-butyllithium In tetrahydrofuran; hexane; toluene at -78 - -65℃; for 2h; Inert atmosphere;	77.8%

methanesulfonic acid (75-75-2) + C36H56FO6SSi4(1-)*Li(1+) → (2S,3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxylmethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1358581-37-9)

Conditions	Yield
In methanol at 20℃; for 10h;	77.6%

methanesulfonic acid (75-75-2) + (2-(4-fluorophenyl)-5-[(5-iodo-2-methylphenyl)methyl]thiophene) (898566-17-1) + (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one (32469-28-6, 55515-28-1, 55515-29-2, 32384-65-9) → (2S,3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxylmethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1358581-37-9)

Conditions	Yield
Stage #1: (2-(4-fluorophenyl)-5-[(5-iodo-2-methylphenyl)methyl]thiophene); (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one With n-butyllithium In tetrahydrofuran; toluene at -85 - -65℃; for 2h; Stage #2: methanesulfonic acid In tetrahydrofuran; methanol; toluene at 20℃; for 16h; Time;	77.5%

methanesulfonic acid (75-75-2) + 2-[(5-bromo-2-methyl-phenyl)methyl]-5-(4-fluorophenyl)thiophene (1030825-20-7) + (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one (32469-28-6, 55515-28-1, 55515-29-2, 32384-65-9) → (2S,3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxylmethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1358581-37-9)

Conditions	Yield
Stage #1: 3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl bromide; (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one With n-butyllithium In tetrahydrofuran; hexane; toluene at -100 - -90℃; for 1h; Inert atmosphere; Stage #2: methanesulfonic acid In tetrahydrofuran; methanol; hexane; toluene at -100 - 20℃;	77%

2-[(5-bromo-2-methyl-phenyl)methyl]-5-(4-fluorophenyl)thiophene (1030825-20-7) + C18H42O6Si4 → (2S,3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxylmethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1358581-37-9)

Conditions	Yield
With tert.-butyl lithium In tetrahydrofuran; toluene; pentane at -78 - -65℃; for 2h; Inert atmosphere;	76.7%

(2-(4-fluorophenyl)-5-[(5-iodo-2-methylphenyl)methyl]thiophene) (898566-17-1) + toluene-4-sulfonic acid (104-15-4) + (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one (32469-28-6, 55515-28-1, 55515-29-2, 32384-65-9) → (2S,3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxylmethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1358581-37-9)

Conditions	Yield
Stage #1: (2-(4-fluorophenyl)-5-[(5-iodo-2-methylphenyl)methyl]thiophene); (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one With n-butyllithium In tetrahydrofuran; toluene at -85 - -65℃; for 2h; Stage #2: toluene-4-sulfonic acid In tetrahydrofuran; methanol; toluene at 20℃; for 16h;	72.4%

methanesulfonic acid (75-75-2) + (2-(4-fluorophenyl)-5-[(5-iodo-2-methylphenyl)methyl]thiophene) (898566-17-1) + 2,3,4,6-tetra-O-acetyl-D-glucono-1,5-lactone (61259-48-1, 73322-42-6) → (2S,3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxylmethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1358581-37-9)

Conditions	Yield
Stage #1: (2-(4-fluorophenyl)-5-[(5-iodo-2-methylphenyl)methyl]thiophene) With TurboGrignard In tetrahydrofuran; toluene at -10 - -5℃; for 2h; Inert atmosphere; Stage #2: 2,3,4,6-tetra-O-acetyl-D-glucono-1,5-lactone In tetrahydrofuran; toluene at -45 - -40℃; for 2h; Inert atmosphere; Stage #3: methanesulfonic acid In methanol at 40℃; for 4h;	37.5%

methanesulfonic acid (75-75-2) + (5-bromo-2-chloro-phenyl)-[5-(4-fluorophenyl)-2-thienyl]methanone (1358581-35-7) + (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one (32469-28-6, 55515-28-1, 55515-29-2, 32384-65-9) → (2S,3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxylmethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1358581-37-9)

Conditions	Yield
Stage #1: (5-bromo-2-chloro-phenyl)-[5-(4-fluorophenyl)-2-thienyl]methanone With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 1h; Stage #2: (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one In tetrahydrofuran; hexane at -78℃; for 2h; Stage #3: methanesulfonic acid In tetrahydrofuran; methanol; hexane at 20℃; for 16h;	36.7%

5-bromo-2-chlorobenzoic acid (21739-92-4) → (2S,3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxylmethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1358581-37-9)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: thionyl chloride / toluene; N,N-dimethyl-formamide / 5 h / 0 - 100 °C 2.1: aluminum (III) chloride / dichloromethane / 16.5 h / -10 - 20 °C 3.1: n-butyllithium / tetrahydrofuran; hexane / 1 h / -78 °C 3.2: 2 h / -78 °C 3.3: 16 h / 20 °C View Scheme

4-fluoroboronic acid (1765-93-1) → (2S,3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxylmethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1358581-37-9)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: tetrakis(triphenylphosphine) palladium(0); potassium carbonate / Dimethyl ether; water / 0.5 h / 100 °C / Microwave irradiation 2.1: aluminum (III) chloride / dichloromethane / 16.5 h / -10 - 20 °C 3.1: n-butyllithium / tetrahydrofuran; hexane / 1 h / -78 °C 3.2: 2 h / -78 °C 3.3: 16 h / 20 °C View Scheme
Multi-step reaction with 5 steps 1.1: tetrabutylammomium bromide; palladium diacetate; potassium carbonate / water / 2 h / 20 °C 2.1: sodium tetrahydroborate; ethanol / 6 h / 20 °C 3.1: thionyl chloride / 3 h / 70 °C 4.1: aluminum (III) chloride / ethyl acetate / 8 h / 80 °C / Cooling with ice 5.1: n-butyllithium / tetrahydrofuran; toluene; hexane / 1 h / -78 °C 5.2: 3 h / -78 °C 5.3: 10 h / -78 - 40 °C View Scheme

2-(4-fluorophenyl)thiophene (58861-48-6) → (2S,3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxylmethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1358581-37-9)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: aluminum (III) chloride / dichloromethane / 16.5 h / -10 - 20 °C 2.1: n-butyllithium / tetrahydrofuran; hexane / 1 h / -78 °C 2.2: 2 h / -78 °C 2.3: 16 h / 20 °C View Scheme

5-bromo-2-chloro-benzoyl chloride (21900-52-7) → (2S,3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxylmethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1358581-37-9)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: aluminum (III) chloride / dichloromethane / 16.5 h / -10 - 20 °C 2.1: n-butyllithium / tetrahydrofuran; hexane / 1 h / -78 °C 2.2: 2 h / -78 °C 2.3: 16 h / 20 °C View Scheme

D-glucono-1,4-lactone (1198-69-2) → (2S,3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxylmethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1358581-37-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: 4-methyl-morpholine / tetrahydrofuran / 1 h / -10 - 45 °C 2: tert.-butyl lithium / tetrahydrofuran; toluene; pentane / 2 h / -78 - -65 °C / Inert atmosphere View Scheme

methanol (67-56-1) + C36H56FO6SSi4(1-)*Li(1+) → (2S,3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxylmethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1358581-37-9)

Conditions	Yield
With hydrogenchloride In 2-methyltetrahydrofuran; hexane; toluene at -10 - -5℃; for 2h; Inert atmosphere;	25 g

(3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one (32469-28-6, 55515-28-1, 55515-29-2, 32384-65-9) → (2S,3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxylmethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1358581-37-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: n-butyllithium / toluene / -18 - -5 °C 2: methanol / 0 - 20 °C View Scheme

2-[(5-bromo-2-methyl-phenyl)methyl]-5-(4-fluorophenyl)thiophene (1030825-20-7) → (2S,3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxylmethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1358581-37-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: n-butyllithium / toluene / -18 - -5 °C 2: methanol / 0 - 20 °C View Scheme

methanesulfonic acid (75-75-2) + 1-[1-hydroxy-2,3,4,6-tetra-O-(trimethylsilyl)-β-D-glucopyranosyl]-4-methyl-3-[[5-(4-fluorophenyl)-2-thienyl]methyl]benzene (1132832-76-8) → (2S,3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxylmethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1358581-37-9)

Conditions	Yield
In methanol at 0 - 20℃;

5-iodo-2-methylbenzoic acid (54811-38-0) → (2S,3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxylmethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1358581-37-9)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: N,N-dimethyl-formamide; thionyl chloride / chlorobenzene / 4 h / 65 - 70 °C / Inert atmosphere; Industrial scale 2.1: aluminum (III) chloride / chlorobenzene / 4 h / 50 - 55 °C / Industrial scale 3.1: aluminum (III) chloride; 1,1,3,3-Tetramethyldisiloxane / chlorobenzene / 10 - 50 °C / Industrial scale 4.1: n-butyllithium / tetrahydrofuran; toluene; hexane / -50 °C 4.2: 3 h / 0 °C 5.1: methanesulfonic acid / 3 h / 15 °C / Industrial scale View Scheme
Multi-step reaction with 5 steps 1.1: N,N-dimethyl-formamide; thionyl chloride / chlorobenzene / 4 h / 65 - 70 °C / Inert atmosphere; Industrial scale 2.1: aluminum (III) chloride / chlorobenzene / 4 h / 50 - 55 °C / Industrial scale 3.1: aluminum (III) chloride; 1,1,3,3-Tetramethyldisiloxane / chlorobenzene / 10 - 50 °C / Industrial scale 4.1: n-butyllithium / tetrahydrofuran; toluene; hexane / -70 °C / Industrial scale 4.2: 3 h / 0 °C / Industrial scale 5.1: methanesulfonic acid / 3 h / 15 °C / Industrial scale View Scheme

5-iodo-2-methylbenzoyl chloride (108440-70-6) → (2S,3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxylmethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1358581-37-9)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: aluminum (III) chloride / chlorobenzene / 4 h / 50 - 55 °C / Industrial scale 2.1: aluminum (III) chloride; 1,1,3,3-Tetramethyldisiloxane / chlorobenzene / 10 - 50 °C / Industrial scale 3.1: n-butyllithium / tetrahydrofuran; toluene; hexane / -50 °C 3.2: 3 h / 0 °C 4.1: methanesulfonic acid / 3 h / 15 °C / Industrial scale View Scheme
Multi-step reaction with 4 steps 1.1: aluminum (III) chloride / chlorobenzene / 4 h / 50 - 55 °C / Industrial scale 2.1: aluminum (III) chloride; 1,1,3,3-Tetramethyldisiloxane / chlorobenzene / 10 - 50 °C / Industrial scale 3.1: n-butyllithium / tetrahydrofuran; toluene; hexane / -70 °C / Industrial scale 3.2: 3 h / 0 °C / Industrial scale 4.1: methanesulfonic acid / 3 h / 15 °C / Industrial scale View Scheme

(5-(4-fluorophenyl)thiophen-2-yl)(5-iodo-2-methylphenyl)methanone → (2S,3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxylmethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1358581-37-9)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: aluminum (III) chloride; 1,1,3,3-Tetramethyldisiloxane / chlorobenzene / 10 - 50 °C / Industrial scale 2.1: n-butyllithium / tetrahydrofuran; toluene; hexane / -50 °C 2.2: 3 h / 0 °C 3.1: methanesulfonic acid / 3 h / 15 °C / Industrial scale View Scheme
Multi-step reaction with 3 steps 1.1: aluminum (III) chloride; 1,1,3,3-Tetramethyldisiloxane / chlorobenzene / 10 - 50 °C / Industrial scale 2.1: n-butyllithium / tetrahydrofuran; toluene; hexane / -70 °C / Industrial scale 2.2: 3 h / 0 °C / Industrial scale 3.1: methanesulfonic acid / 3 h / 15 °C / Industrial scale View Scheme

(2-(4-fluorophenyl)-5-[(5-iodo-2-methylphenyl)methyl]thiophene) (898566-17-1) → (2S,3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxylmethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1358581-37-9)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: n-butyllithium / tetrahydrofuran; toluene; hexane / -70 °C / Industrial scale 1.2: 3 h / 0 °C / Industrial scale 2.1: methanesulfonic acid / 3 h / 15 °C / Industrial scale View Scheme

5-bromo-2-thiophencarboxaldehyde (4701-17-1) → (2S,3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxylmethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1358581-37-9)

Conditions

Yield

Multi-step reaction with 5 steps 1.1: tetrabutylammomium bromide; palladium diacetate; potassium carbonate / water / 2 h / 20 °C 2.1: sodium tetrahydroborate; ethanol / 6 h / 20 °C 3.1: thionyl chloride / 3 h / 70 °C 4.1: aluminum (III) chloride / ethyl acetate / 8 h / 80 °C / Cooling with ice 5.1: n-butyllithium / tetrahydrofuran; toluene; hexane / 1 h / -78 °C 5.2: 3 h / -78 °C 5.3: 10 h / -78 - 40 °C View Scheme

5-(4-fluorophenyl)thiophene-2-carboxaldehyde (249504-38-9) → (2S,3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxylmethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1358581-37-9)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: sodium tetrahydroborate; ethanol / 6 h / 20 °C 2.1: thionyl chloride / 3 h / 70 °C 3.1: aluminum (III) chloride / ethyl acetate / 8 h / 80 °C / Cooling with ice 4.1: n-butyllithium / tetrahydrofuran; toluene; hexane / 1 h / -78 °C 4.2: 3 h / -78 °C 4.3: 10 h / -78 - 40 °C View Scheme

[5-(4-fluorophenyl)thiophen-2-yl]methanol (1225916-69-7) → (2S,3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxylmethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1358581-37-9)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: thionyl chloride / 3 h / 70 °C 2.1: aluminum (III) chloride / ethyl acetate / 8 h / 80 °C / Cooling with ice 3.1: n-butyllithium / tetrahydrofuran; toluene; hexane / 1 h / -78 °C 3.2: 3 h / -78 °C 3.3: 10 h / -78 - 40 °C View Scheme

2-chloromethyl-5-(4-fluorophenyl)thiophene → (2S,3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxylmethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1358581-37-9)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: aluminum (III) chloride / ethyl acetate / 8 h / 80 °C / Cooling with ice 2.1: n-butyllithium / tetrahydrofuran; toluene; hexane / 1 h / -78 °C 2.2: 3 h / -78 °C 2.3: 10 h / -78 - 40 °C View Scheme

methanol (67-56-1) + 1-[1-hydroxy-2,3,4,6-tetra-O-(trimethylsilyl)-β-D-glucopyranosyl]-4-methyl-3-[[5-(4-fluorophenyl)-2-thienyl]methyl]benzene (1132832-76-8) → (2S,3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxylmethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1358581-37-9)

Conditions	Yield
With methanesulfonic acid at -30 - 20℃; Reagent/catalyst; Temperature;	54.9 g

2-[(5-bromo-2-methyl-phenyl)methyl]-5-(4-fluorophenyl)thiophene (1030825-20-7) + (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one (32469-28-6, 55515-28-1, 55515-29-2, 32384-65-9) → (2S,3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxylmethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1358581-37-9)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: N,N,N',N'',N'''-pentamethyldiethylenetriamine; n-butyllithium / tetrahydrofuran / 1 h / -78 °C / Inert atmosphere 1.2: 2 h / -78 °C / Inert atmosphere 2.1: methanol / 10 h / 20 °C View Scheme

(2S,3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxylmethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1358581-37-9) → canagliflozin (842133-18-0)

Conditions	Yield
With triethylsilane; boron trifluoride diethyl etherate In dichloromethane at -40 - 0℃; for 3h;	90%
Stage #1: (2S,3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxylmethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol With aluminum (III) chloride In dichloromethane; acetonitrile at -5℃; for 0.5h; Stage #2: With triethylsilane In dichloromethane; acetonitrile at -5 - 10℃; for 2h;	79%
With triethylsilane; acetonitrile boron trifluoride complex In n-heptane at -5 - 5℃; for 5h;	77.5%

(2S,3R,4S,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxylmethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1358581-37-9) + tert-butyldimethylsilyl chloride (18162-48-6) → (2S,3R,4S,5S,6R)-6-[(tertbutyl(dimethyl)silyl)oxymethyl]-2-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methyl-phenyl]-2-methoxy-tetrahydropyran-3,4,5-triol (1358581-40-4)

Conditions	Yield
With pyridine; dmap for 16h;	89.7%

Upstream product

• 1030825-20-7 3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl bromide 
• 32469-28-6 (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one 
• 75-75-2 methanesulfonic acid 
• 898566-17-1 (2-(4-fluorophenyl)-5-[(5-iodo-2-methylphenyl)methyl]thiophene) 
• 61259-48-1 2,3,4,6-tetra-O-acetyl-D-glucono-1,5-lactone 
• 67-56-1 methanol 
• 1132832-76-8 1-[1-hydroxy-2,3,4,6-tetra-O-(trimethylsilyl)-β-D-glucopyranosyl]-4-methyl-3-[[5-(4-fluorophenyl)-2-thienyl]methyl]benzene 
• 1225916-69-7 [5-(4-fluorophenyl)thiophen-2-yl]methanol 
• 249504-38-9 5-(4-fluorophenyl)thiophene-2-carboxaldehyde 
• 4701-17-1 5-bromo-2-thiophencarboxaldehyde 
• 108440-70-6 5-iodo-2-methylbenzoyl?chloride 
• 54811-38-0 5-iodo-2-methylbenzoic?acid 
• 104-15-4 toluene-4-sulfonic acid 
• 1198-69-2 D-glucono-1,4-lactone 

Downstream Products

• 1358581-42-6 [[(2R,3R,4S,5R,6S)-3,4,5-tribenzyloxy-6-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methyl-phenyl]-6-methoxy-tetrahydropyran-2-yl]methoxy]tert-butyl-dimethyl-silane 
• 1358581-43-7 [(2R,3R,4S,5R,6S)-3,4,5-tribenzyloxy-6-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methyl-phenyl]-6-methoxy-tetrahydropyran-2-yl]methanol 
• 1358581-44-8 (2S,3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methyl-phenyl]-6-methoxy-tetrahydropyran-2-carbaldehyde 
• 1358581-46-0 (2S,3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methyl-phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-carbaldehyde 
• 1358581-50-6 [(3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methyl-phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-yl]methanol 
• 842133-18-0 canagliflozin 
• 1589590-87-3 (2R,3R,4R,5S,6R)-2-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol 
• 1358581-40-4 (2S,3R,4S,5S,6R)-6-[(tertbutyl(dimethyl)silyl)oxymethyl]-2-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methyl-phenyl]-2-methoxy-tetrahydropyran-3,4,5-triol 

Relevant articles and documents

Telescoped lithiation, C-arylation and methoxylation in flow-batch hybrid toward the synthesis of canagliflozin

We report a highly efficient three-step flow-batch hybrid procedure for the synthesis of a key canagliflozin intermediate. The telescoped process provides exquisite control over an exothermic and mixing sensitive lithiation and subsequent C-arylation within a microstructured flow reactor. Methoxylation reagents are then added in flow, before reaching completion in a batch vessel. The flow process afforded the target intermediate in 76% yield, with a throughput of 26.8 g/h.

Preparation method and application of canagliflozin alpha isomer

The invention discloses a preparation method and application of a canagliflozin alpha isomer, the preparation method comprises the following steps: in the presence of Lewis acid, a compound of formulaIV and a reducing agent are subjected to a reduction reaction in an organic solvent to obtain the canagliflozin alpha isomer, wherein the lewis acid is a mixture of trifluoroacetic acid and trimethylsilyl trifluoromethanesulfonate; the reducing agent is 1, 1, 3, 3-tetramethyldisiloxane. The preparation method is simple, the high-purity canagliflozin related substance reference substance can be rapidly obtained, the yield of the product canagliflozin alpha isomer is 37.5%, the purity is as high as 97.61%, the purity requirement of a standard substance is completely met, and the canagliflozin alpha isomer can be used as the standard substance and can be applied to quality control and research of canagliflozin bulk drugs. Therefore, the quality control level of canagliflozin is improved, andthe clinical medicinal safety is ensured.

Method for preparing intermediates of gliflozin hypoglycemic drugs

The invention belongs to the technical field of medicine synthesis, and relates to a novel method for preparing key intermediates of gliflozin hypoglycemic drugs, in particular to a preparation methodof key intermediates (C-1, D-1 and E-1) of canagliflozin, dapagliflozin and empagliflozin. The method comprises the following steps: 1) in the presence of a cosolvent, carrying out halogen metal exchange on a raw material, namely aryl bromide 2 and an organic lithium reagent to obtain an aryl lithium reagent 3, and carrying out a nucleophilic addition reaction on the aryl lithium reagent 3 and TMS-protected glucolactone 4 to obtain a transition product 5; and 2) removing a TMS protecting group from the transition product 5, and converting hemiketal into ketal to obtain the key intermediate 1with a single configuration. According to the method, the key intermediates (C-1, D-1 and E-1) of canagliflozin, dapagliflozin and empagliflozin can be stereoselectively synthesized, reaction yield isrelatively high (more than 75%), and product purity is high (wherein HPLC purity is about 95%); so reduction preparation of a final product in the next step is facilitated.

Preparation method of high-purity canagliflozin intermediate

The invention discloses a preparation method of a high-purity canagliflozin intermediate, which comprises the following steps: reacting a thiophene compound with an alkaline reagent in an inert environment at low temperature, and condensing the reaction product with 2, 3, 4, 6-tetra-O-(trimethylsilyl)-D-glucolactone; dropwise adding a strong acid aqueous solution into the obtained reaction solution, quenching after reaction, separating out an organic phase for concentrating, and performing crystallizing and drying to obtain an intermediate I; reacting the intermediate I with strong acid in methanol to obtain a high-purity canagliflozin intermediate II. By preparing the intermediate I with excellent crystallization performance, the purity of the canagliflozin intermediate II is improved. The operation is simple and convenient, the production process is stable, and industrial production is facilitated.

Preparation method of Canagliflozin intermediate

The invention provides a preparation method of a Canagliflozin intermediate. According to the method, a stable reagent is added to an organic solvent mixing system containing 2-(5-BroMo-2-Methylbenzyl)-5-(4-fluorophenyl)thiophene(compound III) and n-Butyllithium, so that the phenomenon that when the n-Butyllithium is used, reaction products are complex, and more by-products exist, can be improved.The method is stable and high in repetition rate, the purity of the obtained intermediate is as high as 94.7%, the continuous reaction yield can achieve 93.8%, and the preparation method has industrial application prospects.

Preparation method of canagliflozin

The invention relates to a synthesis method of canagliflozin. According to the synthesis method, 4-fluorophenylboronic acid is taken as an initial raw material to be coupled with 5-bromo-thiophene-2-formaldehyde to synthesize 5-(4-fluorophenyl)thiophene-2-formaldehyde, the 5-(4-fluorophenyl)thiophene-2-formaldehyde undergoes reduction and chlorination and then undergoes Friedel-Crafts alkylation reaction with 4-bromotoluene to synthesize 2-(2-methyl-5-bromobenzyl)-5-(4-fluorophenyl)thiophene, and the 2-(2-methyl-5-bromobenzyl)-5-(4-fluorophenyl)thiophene undergoes condensation, etherificationand methoxyl removal with 2,3,4,6-tetra-O-trimethylsilyl-D-gluconolactone to obtain the hypoglycemic drug canagliflozin. The preparation method has the following advantages: compared with the conventional preparation methods, the synthesis process takes the 4-fluorobenzeneboronic acid as an initial raw material, so that the raw material is cheap and easy to get, the process is easy to realize industrialization, the synthesis route is short and the operation is easy; in the synthesis process, bromine is not used or butyl lithium does not need to be used twice, so that the risk of the process can be reduced; in addition, the preparation method is capable of improving the yield of canagliflozin products to 70% or more.

PROCESS FOR THE PREPARATION OF AMORPHOUS FORM OF CANAGLIFLOZIN

The present invention relates to an improved process for the preparation of amorphous form of Canagliflozin with high purity and high yield. Particularly the present invention is related to the direct isolation of amorphous form of Canagliflozin from reaction mixture and also related to purification of amorphous form of Canagliflozin through piperidine-4-carboxylic acid complex of Canagliflozin.

Synthesis and Optimization of Canagliflozin by Employing Quality by Design (QbD) Principles

Efforts toward a synthesis and process optimization of canagliflozin 1 are described. Canagliflozin synthesis was accomplished via purified open ring intermediate 12. The process was optimized by employing quality by design (QbD) methodologies, and a telescopic strategy was executed for the first three and last two steps in a total six-step sequence. Optimization of the Friedel-Craft acylation reaction followed by Lewis acid mediated reductive elimination, n-BuLi mediated C-arylation, and reductive demethoxylation was performed to develop a robust process. These steps were found to be critical; therefore, critical process parameters (CPPs) were identified by employing design of experiment (DoE) methodology. In addition, control strategies for dealing with impurities are described.

Method for continuously preparing canagliflozin by using microreactor one-pot method

The invention discloses a method for continuously preparing canagliflozin by using a microreactor one-pot method. The method is used for continuously preparing the canagliflozin by using the microreactor one-pot method, and microreactors are divided into a unit A, a unit B, a unit C and a unit D. The method comprises the steps of mixing a solution of M1 with n-butyl lithium in the unit A for carrying out a reaction; after the reaction is finished, enabling the reaction product to enter the unit B together with a solution of M3, and carrying out a reaction at the temperature of -15 to -5 DEG C to obtain an intermediate A; enabling reaction liquid containing the intermediate A to enter the unit C together with a methanol solution of methane sulfonic acid, and carrying out a reaction to obtain an intermediate B; enabling reaction liquid containing the intermediate B to directly react with boron trifluoride and triethyl silicane in the unit D to obtain the canagliflozin. The method greatly simplifies the operation steps, shortens the reaction time, greatly reduces the use of various solvents, lowers the production cost, improves the production safety, can realize continuous and automatic production, and is high in product purity and yield, thus being suitable for industrial production.

PROCESS FOR THE PREPARATION OF A PHARMACEUTICAL AGENT

This invention provides a process for preparing canagliflozin, comprising: (a) reacting a tricyclic aromatic derivative and a substituted cyclic ester, quenching and deprotecting the resulting intermediate to provide a compound comprising a substituted tetrahydropyran-tricyciic aromatic derivative, and (b) reducing the tetrahydropyran-tricyclic aromatic derivative to provide canagliflozin. The invention also provides a process for preparing canagliflozin hemihydrate.